The invention relates to a hitherto unknown class of compounds, namely cyclo azaphospha hydrocarbons, which exhibits matrix metalloprotease inhibitory effects, to pharmaceutical compositions comprising said compounds and to the use of said compounds in the manufacture of medicaments.
The matrix metalloproteases (MMP) are a family of zinc containing enzymes capable of breaking down many protenaceous compounds in the extracellular matrix, such as collagen, gelatine, fibronectin, laminin and proteoglucan core protein.
There are at least 23 different MMPs classified according to their domain structure and substrate preferences [Lauer-Fields, Exp. Opin. Ther. Patents, 10, 1873-1884, 2000]. MMP may be classified into four main groups: Collagenases degrade fibrilar collagen; stromelysin degrade proteoglucans and glucoproteins; gelatinases degrade non-fibrilar and degraded collagen, i.e. gelatine; and finally the membrane bound MMPs [O""Brien, J. Med. Chem., 43, 156-166, 2000]. The MMPs share a common multidomain structure, but are glycosylated at different sites and to different extent. All MMPs also share a common zinc-binding motif, HisGluXaaGlyHis, and the differences comprise the presence or absence of structural domains controlling such factors as substrate specificity, inhibitor binding, matrix binding and cell-surface localisation. The nomenclature for MMP is simple as they are named MMP-n, wherein n is an integer starting from 1.
MMP plays an important physiological role in tissue remodelling in normal tissue, e.g. angiogenesis, wound healing, bone resorption, ovulation and embryonic development. In healthy tissue, the activity of MMP is carefully controlled by gene expression, by synthesis of the enzymes in a latent pro-enzyme form, and by co-expression of endogenous tissue inhibitors of MMP (TIMP). Excessive or poorly regulated MMP activity has been implicated in a host of pathological conditions, and there has thus been a large effort to design drugs with MMP inhibitor effects, which could be used to re-establish control of the MMP activity.
Many known MMP inhibitors are peptide derivatives, based on naturally occurring amino acids, and with structural similarities to the cleavage sites in the natural substrates of MMP. Other known MMP inhibitors have less peptidic structure, and may be classified as pseudopeptides or peptidomimetics, e.g. sulfonamides.
Prior art of MMP inhibitors consists of peptidic structures [WO 95/19965 and WO 95/19956]; linear and cyclic sulfonamide compounds, [WO 97/44315, WO 00/09485 and EP 0979 816] and buturic and pentanoic acid derivatives [WO 97/43237, WO 97/43239 and WO 99/61413].
It has surprisingly been found that the novel cyclo azaphospha hydrocarbon derivatives of general formula I are potent inhibitors of MMP.
Accordingly, the present invention relates to a compound of general formula I 
wherein bonds denoted a, b and c independently represents single or double bonds;
m and n are independently 0, 1, 2 or 3, provided that m and n are not both 0;
X is S or O;
R1 is 
wherein E, when present represents a bond, methylene or ethylene optionally substituted with halogen, hydroxy, cyano, nitro, C1-4 alkyl, haloalkyl, hydroxyalkyl, alkoxy or alkylcarbonyl;
s and t are independently 0, 1, 2 or 3;
A and Axe2x80x2 independently represent a bond, or a saturated or unsaturated, optionally substituted cyclic or heterocyclic hydrocarbon di- or triradical;
Y represents a bond, O, S, C(O)NR10, NR10C(O) or NR10, wherein R10 is hydrogen, hydroxy, branched or straight, saturated or unsaturated hydrocarbon radical, optionally substituted with halogen, nitro, cyano, hydroxyl, alkoxy, alkylcarbonyl or alkylamino;
R8 represents a bond, hydrogen, alkanediyl or alkendiyl diradical, one or more ether diradicals (Rxe2x80x2xe2x80x94Oxe2x80x94Rxe2x80x3) or amine diradicals (Rxe2x80x2xe2x80x94Nxe2x80x94Rxe2x80x3), wherein Rxe2x80x2 and Rxe2x80x3 independently represent alkyl or alkenyl with a C-content from 0 to 3;
R9 represents hydrogen, hydroxy, halogen, cyano, nitro, branched or straight, saturated or unsaturated hydrocarbon radical, optionally substituted with halogen, cyano, hydroxyl, alkoxy, alkylcarbonyl or alkylamino; NR11R12, C(O)NR11R12, C(O)R11R12, CO(O)R11R12, S(O)2R11, wherein each R11 and R12 independently represent hydrogen, halogen, a branched or straight, saturated or unsaturated hydrocarbon radical, optionally substituted with halogen, cyano, hydroxyl, alkoxy, alkylcarbonyl or alkylamino;
R2 represents hydroxamic acid, carboxylic acid, phosphonic acid or a mercaptomethyl group;
R3 and R4 each independently represent hydrogen, halogen, cyano, hydroxy, nitro, branched or straight, saturated or unsaturated hydrocarbon radical, optionally substituted with halogen, cyano, nitro, hydroxy; alkoxy, hydroxy, alkylcarbonyl, alkylamino; or R3 and R4 together with the carbon atoms to which they are attached and the connecting nitrogen atom form a heterocyclic ring; each R5, R6, and R7 independently represents hydrogen, hydroxy, nitro, cyano, halogen, branched or straight, saturated or unsaturated hydrocarbon radical, optionally substituted with halogen, cyano, nitro, hydroxyl, alkoxy, alkylcarbonyl or alkylamino; or R4 and R5, R5 and R6 or R6 and R7, together with the carbon atom to which they are attached form a saturated or unsaturated, optionally substituted cyclic or heterocyclic ring;
and pharmaceutically acceptable salts thereof.
In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I, together with a pharmaceutically acceptable excipient.
In still another aspect, the invention relates to a method of treating or preventing diseases or conditions involving tissue breakdown, inflammation or proliferative disorder comprising administering to a patient in need thereof an effective amount of a compound of formula I.
In a still further aspect, the invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment or profylaxis of diseases or conditions involving tissue breakdown, inflammation or proliferative disorder.
The term xe2x80x9chalogenxe2x80x9d when used herein is intended to indicate members of the seventh main group of the periodic table, i.e. flouro, chloro, bromo and iodo.
The term xe2x80x9calkanexe2x80x9d is intended to indicate straight, branched or cyclic compounds, containing carbon and hydrogen, which are saturated. The term includes the subclasses primary, secondary and tertiary alkane, such as methane, ethane, n-propane, iso-butan, tert. butan, cyclohexan, cyclopentan.
The term xe2x80x9calkenexe2x80x9d is intended to indicate straight, branched or cyclic compounds, containing carbon and hydrogen, and with at least one double bond. The term includes primary secondary and tertiary alkene, such as ethene, propene, 1-butene, 2-butene, 3,3-dimethyl-1-butene, cyclopropene, cyclohexen e.
The term xe2x80x9calkylxe2x80x9d is intended to indicate a univalent radical derived from straight, branched or cyclic alkane by removing a hydrogen atom from any carbon atom. The term includes the subclasses primary, secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, isopentyl, isohexyl, cycloheptyl, cyclohexyl, cyclopentyl and cyclopropyl.
The term xe2x80x9chaloalkylxe2x80x9d is intended to indicate partially or fully halogenated alkyl radicals, such as trifluoromethyl.
The term xe2x80x9chydroxyalkylxe2x80x9d is intended to indicate an alkyl substituted with one or more hydroxy groups, such as 2-hydroxyethyl, 2-hydroxypropyl and 2,4-dihydroxypentyl.
The term xe2x80x9calkoxyxe2x80x9d is intended to indicate a radical of formula ORxe2x80x2, wherein Rxe2x80x2 is alkyl as defined above, e.g. methoxy, ethoxy, propoxy, butoxy, etc.
The term xe2x80x9calkoxycarbonylxe2x80x9d is intended to indicate a radical of formula xe2x80x94COORxe2x80x2 wherein Rxe2x80x2 is alkyl as defined above, e.g. methoxycarbonyl, ethoxycabonyl, n-propoxycarbonyl, isopropoxycarbonyl, etc.
The term xe2x80x9csaturated cyclic hydrocarbonxe2x80x9d is intended to indicate cyclic compounds, optionally fused bicyclic rings, containing hydrogen and carbon, which are saturated, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane and decaline.
The term xe2x80x9cunsaturated cyclic hydrocarbonxe2x80x9d is intended to indicate cyclic compounds, optionally fused bicyclic rings, containing hydrogen and carbon, in which one or more carbonxe2x80x94carbon bond is unsaturated, such as cyclopentene, cyclohexene, cyclohexadiene, cycloheptene, benzene, naphtene and 1,4-dihydronaphtene, indane and indene.
The term xe2x80x9cheterocyclic hydrocarbonxe2x80x9d is intended to indicate saturated or unsaturated cyclic compounds of hydrogen, carbon, and one or more heteroatoms selected from O, S and N, such as pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrrolidine, pyridine, pyrimidine, tetrahydrotiophene, tetrahydrofuran, piperidine, piperazine, phosphalane, phosphorinane and phosporepane.
The terms xe2x80x9cmonoradicalxe2x80x9d, xe2x80x9cdiradicalxe2x80x9d and xe2x80x9ctriradicalxe2x80x9d is intended to indicate a moity from which one, two or three hydrogens, respectively, have been removed.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to indicate salts prepared by reacting a compound of formula I with a suitable inorganic or organic acid, e.g. hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, acetic, phosphoric, lactic, maleic, phthalic, citric, propionic, benzoic, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, toluenesulfonic, sulfamic or fumaric acid. Pharmaceutically acceptable salts of compounds of formula I may be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, ammonia, amines or the like.
The term xe2x80x9ceffective amountxe2x80x9d is intended to indicate the amount which is required to confer a therapeutic effect to the treated patient, and is typically determined on the basis of the route of administration; age, body weight, sex, health and condition of the patient; the nature and extend of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the desired effect.
The term xe2x80x9cexcipientxe2x80x9d is intended to indicate all substances in a pharmaceutical formulation which are not active ingredients, such as e.g. carriers, binders, lubricants, thickeners, surface active agents, preservatives, emulsifiers, buffers, flavouring agents or colorants.
The pharmacophore of many MMP inhibitors reported in the literature comprises two elements vital to their function: 1) A zinc binding group, often hydroxamic acid, reverse hydroxamic acid, oxygenated phosphorous groups (e.g. phosphinic acid and phosphonamides including aminophosphonic acid) carboxylic acid, or mercaptomethyl which ligates to the zinc in the active site of the MMP; and 2) groups which can interact with specific subsites near to the active site of MMP [O""Bien, J. Med. Chem, 43, 156-166, 2000; Hajduk, J. Am. Chem. Soc, 119, 5818-5827, 1997]. It is well known that different MMP inhibitors exhibit different selectivity towards the known MMPs. From X-ray analyses of MMPs it emerge that MMPs may be classified into two large subgroups according to the depth of the S1xe2x80x2 subsite or pocket, i.e. either as deep or short S1xe2x80x2 pocket enzymes. The S1xe2x80x2 pocket is also referred to as the xe2x80x9cselectivity pocketxe2x80x9d because the size of the inhibitor moiety interacting with the S1xe2x80x2 pocket, appears to determine the specificity of the inhibitor [Whitaker, Chem. Rev, 99, 2735-2776, 1999]. It is found that large substituents on the inhibitor next to the zinc-binding group enhances inhibitory activity towards deep pocket MMPs, such as MMP-2, MMP-9 and MMP-3, at the expense of short pocket MMPs, such as MMP-1 and MMP-7. However, as all MMPs share a common active site, all MMPs are to some extend inhibited by any MMP inhibitor, and no true selectivity for a single MMP has been achieved [Brown, Exp. Opin. Invest. Drugs, 9, 2167-2177, 2000].
Many highly potent MMP inhibitors have been developed with IC50 in the nanomolar range when tested in vitro. Unfortunately, these compounds show poor bioavailability, and they have thus little use in therapeutic treatments [Brown, Breast Cancer Res. Treat., 52, 125-136, 1998]. Hence, it is still a challenge to develop compounds with the right balance between MMP inhibition, water solubility, oral avilability, pharmacokinetic characteristics, etc required for useful in vivo MMP inhibitors.
It has now surprisingly been found that a novel type of compounds, i.e. cyclo azaphospha hydrocarbons of the general formula I exhibit high MMP inhibitory activity.
In a preferred embodiment, X is O.
In a further preferred embodiment, a and c are both single bonds; b is a double bond; and R4 and R7 are independently either hydrogen or methyl.
In a still further preferred embodiment, E is absent; s and t are both 0; Y is O in the para position on A; A being phenyl.
In a still further preferred embodiment, R2 is hydroxamic acid.
In a still further preferred embodiment, the compound of formula I is selected from the group consisting of
(xc2x1)-N-hydroxy-2-oxo-2-(4-phenoxyphenyl)-azaphosphorin-4-ene-1-acetamide;
(xc2x1)-N-hydroxy-2-oxo-2-(4-phenoxyphenyl)-azaphosphorinane-1-acetamide;
(xc2x1)-N-hydroxy-2-oxo-2-(4-phenyl-azaphosphorep-5-ene-1-acetamide;
(xc2x1)-N-hydroxy-2-oxo-2-(4-phenoxyphenyl)-azaphosphorepane-1-acetamide;
(xc2x1)-N-hydroxy-2-(4-(4-chlorophenoxy)-phenyl-2-oxo-azaphosphorin-4-ene-1-acetamide;
(xc2x1)-N-hydroxy-2-(4-Methoxyphenyl)-2-oxo-azaphosphorolane-1-acetamide;
(xc2x1)-(R*,R*,S*)-N-hydroxy-2-oxo-2-(4-phenoxyphenyl)-1,2-azaphosphabicyclo[4.3.0]non-4-ene-9-carboxamide;
(xc2x1)-N-hydroxy-2-(4-Ethoxyphenyl)-2-oxo-azaphosphoroc-6-ene-1-acetamide;
(xc2x1)-N-hydroxy-2-(4-Ethoxyphenyl)-2-oxo-azaphosphorin-4-ene-1-acetamide;
(xc2x1)-2-(4-Ethoxyphenyl)-2-oxo-azaphosphorin-4-ene-1-acetic acid;
(xc2x1)-N-hydroxy-2-(4-Ethoxyphenyl)-2-oxo-azaphosphorinane-1-acetamide;
(xc2x1)-N-hydroxy-2-(4-Ethoxyphenyl)-2-oxo-azaphosphorocane-1-acetamide;
(xc2x1)-2-(4-Ethoxyphenyl)-2-oxo-azaphosphorep-5-ene-1-acetic acid;
(xc2x1)-N-hydroxy-2-(4-(2-methylpropoxy)-phenyl)-2-oxo-azaphosphorin-4-ene-1-acetamide;
(xc2x1)-N-hydroxy-2-(4-Ethoxyphenyl)-2-oxo-azaphosphorepane-1-acetamide; and
(xc2x1)-N-hydroxy-2-(4-(2-methylpropoxy)-phenyl)-2-oxo-azaphosphorinane-1-acetamide.
Compounds of the general formula I contain asymmetric carbon atoms as well as carbonxe2x80x94carbon double bonds, which allow for isomeric forms. It will be appreciated that the present invention relates to any tautomeric, diastereomeric or optical isomeric form, either in pure form or as mixtures thereof, represented by the formula I.
Imbalance in MMP production or activity has been implicated in many diseases, hence the therapeutic value of MMP inhibitors. Compounds that have the property of inhibiting MMP are thus believed to be potentially useful for treating, preventing and/or ameliorating disease severity, disease symptoms, and/or periodicity of reoccurrence of a disease or condition associated with an imbalance in MMP production or activity. Diseases or conditions include, but are not limited to those involving tissue breakdown or inflammation, such as rheumatoid arthritis, osteoarthritis, osteopenias, such as osteroporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, skin aging, tumour metastasis, tumour invasion and tumour growth; diseases associated with neuroinflammatory disorder, including those involving myelin degradation, such as multiple sclerosis; angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth, psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angiofibromas and hemangiomas [Vu in Metalloproteases, Parks and Mecham (Eds.), 115-148, 1998, Academic Press; Mullins, Biochem. Biophys. Acta, 695, 117-214, 1983; Henderson, Drugs of the Future, 15, 495-508, 1990; Reich, Cancer Res, 48, 3307-3312, 1988; Whitaker, Chem. Rev., 99, 2735-2776, 1999].
Moreover, MMP inhibitors are also potentially useful for treating, preventing and/or ameliorating disease severity, disease symptoms, and/or periodicity of reoccurrence of a disease or condition associated excess Tumour Necrosis Factor xcex1 (TNF-xcex1) production [Whitaker, Chem. Rev., 99, 2735-2776, 1999]. TNF-xcex1 is a potent proinflammatory cytokine which has been implicated in inflammatory diseases or conditions, arthritis, asthma, septic shock, fever, cardiovascular effects, haemorrage, coagulation, acute phase reponse and apoptosis. TNF-xcex1 is expressed in the cells as a membrane-bound 26 kDa protein, which is proteolytically cleaved to release a 17 kDa active, soluble form. The TNF-xcex1 processing is catalysed by the enzyme TNF-xcex1 convertase (TACE), which is a metalloprotease, and several MMP inhibitors have been found to inhibit TNF-xcex1 processing [Mohler, Nature, 370, 218, 1994]. Excess TNF-xcex1 production can thus potentially be controlled by treatment with an MMP inhibitor.
In another aspect, the invention relates to a pharmaceutical formulation of a compound of formula I. The formulations of the present invention, both for veterinary and for human medical use, comprise active ingredients in association with a pharmaceutically acceptable carrier(s) and optionally other therapeutic ingredient(s). The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
The formulations include e.g. those in a form suitable for oral (including sustained or timed release), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intraarticular and intravenous), transdermal, ophthalmic, topical, nasal or buccal administration.
By the term xe2x80x9cdosage unitxe2x80x9d is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.
The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy, e.g as disclosed in Remington, The Science and Practise of Pharmacy, 20th ed., 2000. All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid, such as ethanol or glycerol; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Such oils may be edible oils, such as e.g. cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose and polyvinylpyrrolidone. The active ingredients may also be administered in the form of a bolus, electuary or paste.
A tablet may be made by compressing or moulding the active ingredient optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient(s) in a free-flowing form such as a powder or granules, optionally mixed by a binder, such as e.g. lactose, glucose, starch, gelatine, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose polyethylene glycol, waxes or the like; a lubricant such as e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like; a disintegrating agent such as e.g. starch, methyl cellulose, agar, bentonite, xanthan gum or the like or dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier moistened with an inert liquid diluent.
Formulations for rectal administration, e.g. injection or infusion, may be in the form of a suppository incorporating the active ingredients and a carrier, or in the form of an enema.
Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredients, which is preferably isotonic with the blood of the recipient, e.g. isotonic saline, isotonic glucose solution or buffer solution. The formulation may be conveniently sterilised by for instance filtration through a bacteria retaining filter, addition of sterilising agent to the formulation, irradiation of the formulation or heating of the formulation. Liposomal formulations as disclosed in e.g. U.S. Pat. Nos. 5,534,499, 5,762,958 and 6,007,839 are also suitable for parenteral administration.
Alternatively, the compound of formula I may be presented as a sterile, solid preparation, e.g. a freeze-dried powder, which is readily dissolved in a sterile solvent immediately prior to use.
Transdermal formulations may be in the form of a plaster.
Formulations suitable ophthalmic administration may be in the form of a sterile aqueous preparation of the active ingredients, which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for ophthalmic administration.
Formulations suitable for topical or ophthalmic administration include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.
Formulations suitable for nasal or buccal administration include powder, self-propelling and spray formulations, such as aerosols and atomisers.
In addition to the formulations described previously, the compound of formula I may also be presented as a depot preparation. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscular) or by intramuscular injection. Thus, for example, the compound of formula I may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil), with ion exchange resin, or with sparingly soluble derivatives, for example as a sparingly soluble salt.
In the systemic treatment using the present invention daily doses of from 0.001-200 mg per kilogram body weight, preferably from 0.002-50 mg/kg of mammal body weight, for example 0.003-20 mg/kg of a compound of formula I is administered, typically corresponding to a daily dose for an adult human of from 0.2 to 750 mg. In the topical treatment of dermatological disorders, ointments, creams or lotions containing from 0.1-750 mg/g, and preferably from 0.1-500 mg/g, for example 0.1 200 mg/g of a compound of formula I is administered. For topical use in ophthalmology ointments, drops or gels containing from 0.1-750 mg/g, and preferably from 0.1-500 mg/g, for example 0.1-200 mg/g of a compound of formula I is administered. The oral compositions are formulated, preferably as tablets, capsules, or drops, containing from 0.05-250 mg, preferably from 0.1-125 mg, of a compound of formula I per dosage unit.
In addition to the aforementioned ingredients, the formulations of a compound of formula I may include one or more additional ingredients such as diluents, buffers, flavouring agents, colourant, surface active agents, thickeners, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
The invention also includes incorporating other pharmaceutically active ingredients, normally used in the treatment, into the formulation of the present invention. Without limitations, such other pharmaceutically active ingredients may be anti-cancer drugs, such as chemotherapeutic agents, hormonal agents, or biological response modifiers.
A crucial step in the synthesis of compounds of formula II, a subclass of compounds of formula I, 
wherein R1, R2, R6, R7, X, b, c and m are as described above, is the Ag+ catalysed stereoselective (the substituents on the pyrrolidine ring are positioned cis) cyclization of aminophospha allenes, as described in scheme 7, step 2. Huby, J. Chem. Soc, Perkin Trans., 1, 145-155, 1991 discloses an Ag+ catalysed steroeselective cyclization of allenic derivatives, wherein the nitrogen is part of a sulfonamide or a carbamate group, whereas the cyclization falls when the nitrogen id part of a formamide or a secondary amine. When the nitrogen is part of a free amine, stereoselectivity is lost.
The present inventors have surprisingly found that Ag-salts catalyse the stereoselective cyclization of phosphonamidic allenes. Accordingly, it is possible to prepare a compound of formula II by catalytically converting a compound of formula III 
wherein R1, R2, R6, R7, X, and m are as described above.
This Ag+ catalysed cyclization may be run under various conditions. Preferably, it is run at temperatures ranging from 0-40xc2x0 C., e.g. 10-30xc2x0 C. The amount of Ag+ salt used ranges from 0.05-2 equivalents, e.g. 0.5-1.5, with respect to the allene. The cyclization may run for any amount of time required to reach the transformation needed and may involve more than one addition of Ag salt. Useful Ag salts may be selected from the group consisting of AgOCOCF3, AgClO4, AgOSO2CF3, AgNO3 and AgBF4.
The invention is further illustrated by the following non-limiting examples.